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1.
Int J Cancer ; 146(7): 1862-1878, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31696517

RESUMO

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.


Assuntos
Biomarcadores Tumorais , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/genética , Transcriptoma , Linhagem Celular Tumoral , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
2.
J Neurosci ; 39(36): 7132-7154, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31350259

RESUMO

Ca2+-activated K+ channels (BK and SK) are ubiquitous in synaptic circuits, but their role in network adaptation and sensory perception remains largely unknown. Using electrophysiological and behavioral assays and biophysical modeling, we discover how visual information transfer in mutants lacking the BK channel (dSlo- ), SK channel (dSK- ), or both (dSK- ;; dSlo- ) is shaped in the female fruit fly (Drosophila melanogaster) R1-R6 photoreceptor-LMC circuits (R-LMC-R system) through synaptic feedforward-feedback interactions and reduced R1-R6 Shaker and Shab K+ conductances. This homeostatic compensation is specific for each mutant, leading to distinctive adaptive dynamics. We show how these dynamics inescapably increase the energy cost of information and promote the mutants' distorted motion perception, determining the true price and limits of chronic homeostatic compensation in an in vivo genetic animal model. These results reveal why Ca2+-activated K+ channels reduce network excitability (energetics), improving neural adaptability for transmitting and perceiving sensory information.SIGNIFICANCE STATEMENT In this study, we directly link in vivo and ex vivo experiments with detailed stochastically operating biophysical models to extract new mechanistic knowledge of how Drosophila photoreceptor-interneuron-photoreceptor (R-LMC-R) circuitry homeostatically retains its information sampling and transmission capacity against chronic perturbations in its ion-channel composition, and what is the cost of this compensation and its impact on optomotor behavior. We anticipate that this novel approach will provide a useful template to other model organisms and computational neuroscience, in general, in dissecting fundamental mechanisms of homeostatic compensation and deepening our understanding of how biological neural networks work.


Assuntos
Retroalimentação Fisiológica , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Células Fotorreceptoras de Invertebrados/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Potenciais Sinápticos , Percepção Visual , Animais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Feminino , Interneurônios/metabolismo , Interneurônios/fisiologia , Modelos Neurológicos , Células Fotorreceptoras de Invertebrados/fisiologia , Canais de Potássio Shab/metabolismo , Superfamília Shaker de Canais de Potássio/metabolismo , Vias Visuais/metabolismo , Vias Visuais/fisiologia
3.
Elife ; 62017 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-28870284

RESUMO

Small fly eyes should not see fine image details. Because flies exhibit saccadic visual behaviors and their compound eyes have relatively few ommatidia (sampling points), their photoreceptors would be expected to generate blurry and coarse retinal images of the world. Here we demonstrate that Drosophila see the world far better than predicted from the classic theories. By using electrophysiological, optical and behavioral assays, we found that R1-R6 photoreceptors' encoding capacity in time is maximized to fast high-contrast bursts, which resemble their light input during saccadic behaviors. Whilst over space, R1-R6s resolve moving objects at saccadic speeds beyond the predicted motion-blur-limit. Our results show how refractory phototransduction and rapid photomechanical photoreceptor contractions jointly sharpen retinal images of moving objects in space-time, enabling hyperacute vision, and explain how such microsaccadic information sampling exceeds the compound eyes' optical limits. These discoveries elucidate how acuity depends upon photoreceptor function and eye movements.


Assuntos
Drosophila melanogaster/fisiologia , Movimentos Oculares/fisiologia , Estimulação Luminosa , Visão Ocular/fisiologia , Acuidade Visual/fisiologia , Animais , Simulação por Computador , Drosophila melanogaster/ultraestrutura , Fixação Ocular/fisiologia , Modelos Neurológicos , Movimento , Fótons , Células Fotorreceptoras de Invertebrados/metabolismo , Células Fotorreceptoras de Invertebrados/ultraestrutura , Retina/fisiologia
4.
J Physiol ; 595(16): 5425-5426, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28809044
5.
Physiol Rep ; 5(11)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28596301

RESUMO

Refractory period (RP) plays a central role in neural signaling. Because it limits an excitable membrane's recovery time from a previous excitation, it can restrict information transmission. Classically, RP means the recovery time from an action potential (spike), and its impact to encoding has been mostly studied in spiking neurons. However, many sensory neurons do not communicate with spikes but convey information by graded potential changes. In these systems, RP can arise as an intrinsic property of their quantal micro/nanodomain sampling events, as recently revealed for quantum bumps (single photon responses) in microvillar photoreceptors. Whilst RP is directly unobservable and hard to measure, masked by the graded macroscopic response that integrates numerous quantal events, modeling can uncover its role in encoding. Here, we investigate computationally how RP can affect encoding of graded neural responses. Simulations in a simple stochastic process model for a fly photoreceptor elucidate how RP can profoundly contribute to nonlinear gain control to achieve a large dynamic range.


Assuntos
Modelos Neurológicos , Células Fotorreceptoras de Invertebrados/fisiologia , Período Refratário Eletrofisiológico , Adaptação Fisiológica , Animais , Drosophila/fisiologia , Visão Ocular
6.
J Physiol ; 595(16): 5439-5456, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28369994

RESUMO

Light intensities (photons s-1  µm-2 ) in a natural scene vary over several orders of magnitude from shady woods to direct sunlight. A major challenge facing the visual system is how to map such a large dynamic input range into its limited output range, so that a signal is neither buried in noise in darkness nor saturated in brightness. A fly photoreceptor has achieved such a large dynamic range; it can encode intensity changes from single to billions of photons, outperforming man-made light sensors. This performance requires powerful light adaptation, the neural implementation of which has only become clear recently. A computational fly photoreceptor model, which mimics the real phototransduction processes, has elucidated how light adaptation happens dynamically through stochastic adaptive quantal information sampling. A Drosophila R1-R6 photoreceptor's light sensor, the rhabdomere, has 30,000 microvilli, each of which stochastically samples incoming photons. Each microvillus employs a full G-protein-coupled receptor signalling pathway to adaptively transduce photons into quantum bumps (QBs, or samples). QBs then sum the macroscopic photoreceptor responses, governed by four quantal sampling factors (limitations): (i) the number of photon sampling units in the cell structure (microvilli), (ii) sample size (QB waveform), (iii) latency distribution (time delay between photon arrival and emergence of a QB), and (iv) refractory period distribution (time for a microvillus to recover after a QB). Here, we review how these factors jointly orchestrate light adaptation over a large dynamic range.


Assuntos
Dípteros/fisiologia , Células Fotorreceptoras de Invertebrados/fisiologia , Animais , Biomimética , Luz , Microvilosidades/fisiologia , Fótons , Células Fotorreceptoras de Invertebrados/ultraestrutura , Processos Estocásticos
7.
J Physiol ; 595(16): 5427-5437, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28233315

RESUMO

A photoreceptor's information capture is constrained by the structure and function of its light-sensitive parts. Specifically, in a fly photoreceptor, this limit is set by the number of its photon sampling units (microvilli), constituting its light sensor (the rhabdomere), and the speed and recoverability of their phototransduction reactions. In this review, using an insightful constructionist viewpoint of a fly photoreceptor being an 'imperfect' photon counting machine, we explain how these constraints give rise to adaptive quantal information sampling in time, which maximises information in responses to salient light changes while antialiasing visual signals. Interestingly, such sampling innately determines also why photoreceptors extract more information, and more economically, from naturalistic light contrast changes than Gaussian white-noise stimuli, and we explicate why this is so. Our main message is that stochasticity in quantal information sampling is less noise and more processing, representing an 'evolutionary adaptation' to generate a reliable neural estimate of the variable world.


Assuntos
Dípteros/fisiologia , Células Fotorreceptoras de Invertebrados/fisiologia , Animais , Luz
8.
Front Comput Neurosci ; 10: 61, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27445779

RESUMO

Many diurnal photoreceptors encode vast real-world light changes effectively, but how this performance originates from photon sampling is unclear. A 4-module biophysically-realistic fly photoreceptor model, in which information capture is limited by the number of its sampling units (microvilli) and their photon-hit recovery time (refractoriness), can accurately simulate real recordings and their information content. However, sublinear summation in quantum bump production (quantum-gain-nonlinearity) may also cause adaptation by reducing the bump/photon gain when multiple photons hit the same microvillus simultaneously. Here, we use a Random Photon Absorption Model (RandPAM), which is the 1st module of the 4-module fly photoreceptor model, to quantify the contribution of quantum-gain-nonlinearity in light adaptation. We show how quantum-gain-nonlinearity already results from photon sampling alone. In the extreme case, when two or more simultaneous photon-hits reduce to a single sublinear value, quantum-gain-nonlinearity is preset before the phototransduction reactions adapt the quantum bump waveform. However, the contribution of quantum-gain-nonlinearity in light adaptation depends upon the likelihood of multi-photon-hits, which is strictly determined by the number of microvilli and light intensity. Specifically, its contribution to light-adaptation is marginal (≤ 1%) in fly photoreceptors with many thousands of microvilli, because the probability of simultaneous multi-photon-hits on any one microvillus is low even during daylight conditions. However, in cells with fewer sampling units, the impact of quantum-gain-nonlinearity increases with brightening light.

9.
Chemosphere ; 144: 2004-12, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26551198

RESUMO

Formaldehyde exposure is toxic to the brains of mammals, but the mechanism remains unclear. We investigated the effects of inhaled formaldehyde on anxiety, depression, cognitive capacity and central levels of glucocorticoid receptor and tyrosine hydroxylase in mice. After exposure to 0, 1 or 2 ppm gaseous formaldehyde for one week, we measured anxiety-like behavior using open field and elevated plus-maze tests, depression-like behavior using a forced swimming test, learning and memory using novel object recognition tests, levels of glucocorticoid receptors in the hippocampus and tyrosine hydroxylase in the Arc, MPOA, ZI and VTA using immuhistochemistry. We found that inhalation of 1 ppm formaldehyde reduced levels of anxiety-like behavior. Inhalation of 2 ppm formaldehyde reduced body weight, but increased levels of depression-like behavior, impaired novel object recognition, and lowered the numbers of glucocorticoid receptor immonureactive neurons in the hippocampus and tyrosine hydroxylase immonureactive neurons in the ventral tegmental area and the zona incerta, medial preoptic area. Different concentrations of gaseous formaldehyde result in different effects on anxiety, depression-like behavior and cognition ability which may be associated with alterations in hippocampal glucocorticoid receptors and brain tyrosine hydroxylase levels.


Assuntos
Encéfalo/efeitos dos fármacos , Formaldeído/toxicidade , Receptores de Glucocorticoides/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Ansiedade/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Cognição/fisiologia , Depressão/metabolismo , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos
10.
J Anat ; 227(2): 243-54, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26110655

RESUMO

All sensory receptors adapt, i.e. they constantly adjust their sensitivity to external stimuli to match the current demands of the natural environment. Electrophysiological responses of sensory receptors from widely different modalities seem to exhibit common features related to adaptation, and these features can be used to examine the underlying sensory transduction mechanisms. Among the principal senses, mechanosensation remains the least understood at the cellular level. To gain greater insights into mechanosensory signalling, we investigated if mechanosensation displayed adaptive dynamics that could be explained by similar biophysical mechanisms in other sensory modalities. To do this, we adapted a fly photoreceptor model to describe the primary transduction process for a stretch-sensitive mechanoreceptor, taking into account the viscoelastic properties of the accessory muscle fibres and the biophysical properties of known mechanosensitive channels (MSCs). The model's output is in remarkable agreement with the electrical properties of a primary ending in an isolated decapsulated spindle; ramp-and-hold stretch evokes a characteristic pattern of potential change, consisting of a large dynamic depolarization during the ramp phase and a smaller static depolarization during the hold phase. The initial dynamic component is likely to be caused by a combination of the mechanical properties of the muscle fibres and a refractory state in the MSCs. Consistent with the literature, the current model predicts that the dynamic component is due to a rapid stress increase during the ramp. More novel predictions from the model are the mechanisms to explain the initial peak in the dynamic component. At the onset of the ramp, all MSCs are sensitive to external stimuli, but as they become refractory (inactivated), fewer MSCs are able to respond to the continuous stretch, causing a sharp decrease after the peak response. The same mechanism could contribute a faster component in the 'sensory habituation' of mechanoreceptors, in which a receptor responds more strongly to the first stimulus episode during repetitive stimulation.


Assuntos
Adaptação Fisiológica/fisiologia , Mecanorreceptores/fisiologia , Mecanotransdução Celular/fisiologia , Células Fotorreceptoras/fisiologia , Animais , Eletrofisiologia , Mamíferos/fisiologia , Modelos Biológicos , Modelos Teóricos , Fusos Musculares/fisiologia
11.
J Neurosci ; 34(21): 7216-37, 2014 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-24849356

RESUMO

Sensory neurons integrate information about the world, adapting their sampling to its changes. However, little is understood mechanistically how this primary encoding process, which ultimately limits perception, depends upon stimulus statistics. Here, we analyze this open question systematically by using intracellular recordings from fly (Drosophila melanogaster and Coenosia attenuata) photoreceptors and corresponding stochastic simulations from biophysically realistic photoreceptor models. Recordings show that photoreceptors can sample more information from naturalistic light intensity time series (NS) than from Gaussian white-noise (GWN), shuffled-NS or Gaussian-1/f stimuli; integrating larger responses with higher signal-to-noise ratio and encoding efficiency to large bursty contrast changes. Simulations reveal how a photoreceptor's information capture depends critically upon the stochastic refractoriness of its 30,000 sampling units (microvilli). In daylight, refractoriness sacrifices sensitivity to enhance intensity changes in neural image representations, with more and faster microvilli improving encoding. But for GWN and other stimuli, which lack longer dark contrasts of real-world intensity changes that reduce microvilli refractoriness, these performance gains are submaximal and energetically costly. These results provide mechanistic reasons why information sampling is more efficient for natural/naturalistic stimulation and novel insight into the operation, design, and evolution of signaling and code in sensory neurons.


Assuntos
Transdução de Sinal Luminoso/fisiologia , Luz , Células Fotorreceptoras de Invertebrados/fisiologia , Percepção Visual/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Cor , Simulação por Computador , Dípteros , Relação Dose-Resposta à Radiação , Processamento Eletrônico de Dados , Feminino , Masculino , Microvilosidades/fisiologia , Modelos Biológicos , Estimulação Luminosa , Células Fotorreceptoras de Invertebrados/classificação , Razão Sinal-Ruído , Fatores de Tempo
12.
Curr Biol ; 22(15): 1371-80, 2012 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-22704990

RESUMO

BACKGROUND: In fly photoreceptors, light is focused onto a photosensitive waveguide, the rhabdomere, consisting of tens of thousands of microvilli. Each microvillus is capable of generating elementary responses, quantum bumps, in response to single photons using a stochastically operating phototransduction cascade. Whereas much is known about the cascade reactions, less is known about how the concerted action of the microvilli population encodes light changes into neural information and how the ultrastructure and biochemical machinery of photoreceptors of flies and other insects evolved in relation to the information sampling and processing they perform. RESULTS: We generated biophysically realistic fly photoreceptor models, which accurately simulate the encoding of visual information. By comparing stochastic simulations with single cell recordings from Drosophila photoreceptors, we show how adaptive sampling by 30,000 microvilli captures the temporal structure of natural contrast changes. Following each bump, individual microvilli are rendered briefly (~100-200 ms) refractory, thereby reducing quantum efficiency with increasing intensity. The refractory period opposes saturation, dynamically and stochastically adjusting availability of microvilli (bump production rate: sample rate), whereas intracellular calcium and voltage adapt bump amplitude and waveform (sample size). These adapting sampling principles result in robust encoding of natural light changes, which both approximates perceptual contrast constancy and enhances novel events under different light conditions, and predict information processing across a range of species with different visual ecologies. CONCLUSIONS: These results clarify why fly photoreceptors are structured the way they are and function as they do, linking sensory information to sensory evolution and revealing benefits of stochasticity for neural information processing.


Assuntos
Drosophila/fisiologia , Microvilosidades/fisiologia , Células Fotorreceptoras de Invertebrados/fisiologia , Adaptação Fisiológica , Animais , Drosophila/ultraestrutura , Retroalimentação Fisiológica , Modelos Biológicos , Células Fotorreceptoras de Invertebrados/ultraestrutura , Processos Estocásticos
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